Although sunlight exposure has been implicated in risk of cutaneous malignant melanoma (CMM), the exact role of ultraviolet light (UV in the etiology of CMM remains unclear. Host susceptibility to UV damage may also play an important role. Based on the high frequency of melanoma and other a skin cancer in xeroderma pigmentosum patients, we hypothesize that cellular DNA repair plays a role in the etiology of UV-induced human melanoma. This hypothesis is supported by the finding of our pilot studies that lymphocytes from melanoma patients tend to have low capacity to repair UV-induced DNA damage. To test this hypothesis, we propose to conduct a molecular epidemiologic study of melanoma using a case-control study design to measure the DNA repair capacity in peripheral lymphocytes. Three hundred untreated melanoma cases and 300 age-and-sex-matched controls without cancer will be included in this steady. A self-administered risk- factor questionnaire will be used for data collection and a 30-ml blood sample drawn for laboratory assays for each subject. The data analysis will emphasize sunlight exposure and age stratification, which will integrate with DNA repair capacity to evaluate genetic susceptibility to CMM. Logistic regression analysis will be used to adjust for possible confounding effects of other known risk factors such as family history of CMM, skin type, and skin lesions including dysplastic nevi. A subset of 200 subjects based on their DNA repair capacities measured will be also assayed for UN-induced in vitro mutagen sensitivity for the levels of expression of four DNA repair genes (XPOC, hMSH2, XRCC1, and ERCC1). This approach will allow us to explore the complementary use of these assays in identifying individuals at high risk of CMM. Our specific aims are: (1) to construct detailed epidemiologic and clinical profiles of CMM cases and controls; (2) to determine the association between cellular DNA repair capacity for UV damage and the risk of CMM by using a case-control study design; (3) to study in vitro UV-induced sensitivity and expression of DNA repair genes in a subset of cases and controls expressing high and low repair capacity; and (4) to evaluate the relationship of DNA repair capacity, UV-induced chromosome sensitivity, and DNA-repair gene expression to epidemiologic and clinical data on CMM. This study will help us understand host susceptibility, particularly the role of DNA repair, in the etiology of CMM. The long-term goal of this study is to identify susceptibility markers for the assessment of CMM risk and to identify individuals at high risk of CMM for future cancer-prevention programs.